Nemorubicin hydrochloride, chemical names (8S-cis, 2″S)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[2,3,6-trideoxy-3-(2-methoxy-4-morpholinyl)-α-L-Iyxo-hexopyranosyl]oxy}-5,12-naphthacenedione hydrochloride and 3′desamino-3′[2(S)methoxy-4-morpholinyl]doxorubicin-hydrochloride (below referred to as nemorubicin hydrochloride only) of formula
is a doxorubicin derivative obtained with the substitution of the —NH2 at position 3° in the sugar moiety with a methoxymorpholino group. The compound was synthesized in the course of a research program aimed at identifying new anthracyclines with at least partially novel modes of action, and possessing broad spectrum of activity, including activity on multidrug resistant tumors and lower toxicity than doxorubicin as far as cardiotoxicity is concerned. U.S. Pat. No. 4,672,057 discloses and claims nemorubicin hydrochloride, preparation process, pharmaceutical compositions and medical uses thereof.
According to WO 00/15203, nemorubicin hydrochloride can be administered via the hepatic artery, for example, as an infusion of from about 15 min to about 30 min every 4 weeks or preferably, as a 5-10 min bolus every 4-8 weeks, to adult patients with either a hepatic metastatic cancer, for example, patients with colorectal cancer who have progressed after receiving intravenous chemotherapy or intrahepatic 5-fluorouracil or 5-fluorodeoxyuridine (FUDR) chemotherapy, or patients with primary liver carcinoma such as, for example, hepatocellular carcinoma or cholangiocarcinoma involving the liver. According to WO 00/15203, nemorubicin hydrochloride can be administered to a patient in a dosage ranging from, e.g., about 100 mcg/m2 to about 1000 mcg/m2, preferably from about 100 mcg/m2 to about 800 mcg/m2, for example, in a dosage of about 200 mcg/m2.
WO 04/75904 describes and claims the use of nemorubicin hydrochloride for the preparation of a medicament for the treatment of a human liver tumor, which comprises intrahepatic administration of nemorubicin hydrochloride via the hepatic artery in a dosage ranging from, e.g., about 100 mcg/m2 to about 800 mcg/m2, preferably from about 200 mcg/m2 to about 600 mcg/m2, for example in a dosage of about 200, 400 or 600 mcg/m2 every 6 weeks.
Two administration schedules have been evaluated in Phase I setting: in one trial nemorubicin hydrochloride was administered by intra-hepatic artery (IHA) as a 30-min infusion every 4 weeks in saline; in another trial, nemorubicin hydrochloride was administered by IHA with iodinated oil as a 5 to 10 min infusion every 6-8 weeks. As described in WO 04/082579 and WO 00/066093, nemorubicin hydrochloride is indicated as a component of therapy in combination with radiotherapy, an alkylating agent, an antimetabolite, a topoisomerase I/II inhibitor or a platinum derivative. Suarato, A et al., ACS Symposium Series (1995), 574 (Anthracycline Antibiotics), pages 142-55 and U.S. Pat. No. 5,304,687 disclose key intermediates and processes for an improved synthesis of nemorubicin hydrochloride.
CN 101011341 and CN 1923284 (Jinan Kangquan Pharmaceutical Science and Technology Co., Ltd.) disclose slow release injections, which comprise microspheres or microballoons that consist of anti-cancer active ingredients and slow-releasing adjuvants and dissolvents.
Nemorubicin Hydrochloride Antitumor Activity
Nemorubicin hydrochloride is a DNA-intercalator, different from classical anthracyclines, in that it works primarily through topoisomerase I as demonstrated by the dominant DNA lesions produced being single strand DNA breaks. The compound shows efficacy on tumors resistant to different anticancer drugs such as platinum derivatives, alkylating agents, topoisomerase I and II inhibitors, taxanes, anthracyclines and vinca alkaloids. In addition, unlike alkylating agents and platinum derivatives, it is effective on cells with upregulation of the nucleotide excision repair pathway or with mismatch repair deficiency.
Nemorubicin hydrochloride was selected for clinical evaluation based on its broad spectrum of activity in experimental models and lower cardiotoxicity than doxorubicin at equally myelotoxic doses in animals.
When nemorubicin hydrochloride was administered intravenously (IV) as single agent to patients, in Phase I-II clinical study setting, anticancer activity was observed in head & neck, cervix and colorectal cancer (in Phase I studies). In Phase I B studies, partial responses (PRs) were reported in non-small-cell-lung cancer, renal cancer and cancer of unknown origin. Regressions were repeatedly reported in liver lesions from primary colorectal and renal cancer. In a Phase II study in sarcomas, 2 PRs were reported out of 26 patients that could be taken into account. In the Phase II investigations in breast cancer patients with liver metastases, 4 objective responses out of 7 treated patients were observed overall. The level of antitumor activity achieved in this study was strongly indicative of the efficacy of nemorubicin hydrochloride in liver lesions and supported further investigation in primary and secondary liver cancer.
Clinical Studies as Single Agent by Intra-Hepatic Artery (IHA) Route
The findings of efficacy in liver lesions reported in the Phase I-II studies by the IV route, coupled with evidence of antitumor efficacy in liver in preclinical models, provided the rationale for specific investigation in hepatocellular carcinoma (HCC). The loco regional approach was chosen in order to decrease the systemic toxicity reported after IV administration.
One Phase I study with saline as a vehicle was conducted by IHA in Europe in patients with HCC and with liver metastases from other solid primary tumors. In addition, one Phase I/II study and one Phase II/III randomized study by IHA route, both with iodinated oil (Lipiodol®) as vehicle, were performed in China in patients with unresectable HCC (Pacciarini, M A et al., Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S, 2006: 14116).
Overall, considering the collective clinical experience gained with nemorubicin hydrochloride administered by IHA route (with and without iodinated oil) to patients with HCC, in Europe and China, 57 HCC patients were taken into account for efficacy. Focusing on perfused liver lesions, there were overall 11/57 confirmed CR/PRs (i.e. a RR of 19.3%, 95% c.i. 10.0-31.9%) lasting from 1 to 54+ months. Disease stabilizations lasting ≧3 months (median duration 4.5 months, range 3-12.5) were reported in 17/57 patients, most of whom had advanced stages of the disease (AJCC Stage III, IIIA and IVA). As far as safety is concerned, nemorubicin hydrochloride showed a manageable safety profile in terms of hematological and hepatic toxicity, as well as nausea and vomiting. The good tolerability and the level of antitumor activity achieved in these studies was strongly supportive of the use of nemorubicin hydrochloride by loco regional approach for the treatment of tumor lesions.
Chemoembolization
In the field of loco regional therapies chemoembolization is a minimally invasive approach for palliative treatment of unresectable tumors. The tumors referred to are primary or metastasis cancers, sarcoma or carcinosarcoma found in brain, central nervous system, kidneys, liver, gall bladders, head and neck, oral cavity, thyroid, skin, mucous membranes, glandular organs, blood vessels, bone tissues, lymph nodes, lungs, esophagus, stomach, lacteal glands, pancreas, eyes, nasopharynge, womb, ovaries, endometrium, cervix, prostate gland, bladders, colon and rectum.
Chemoembolization is also employed as an adjunctive therapy to liver resection or as a bridge to liver transplantation, as well as prior to radiofrequency ablation (Aoki, T et al., Arch Surg. 2004 July; 139(7):766-74; Bruix, J et al. Gastroenterology. 2004 November; 127:S179-88). Chemoembolization has become one of the most commonly performed procedures in interventional radiology.
Chemoembolization typically involves the injection of chemotherapeutic agents, with or without lipiodol and/or embolic agents, into the blood vessels supplying the tumor, e.g. into the branch of the hepatic artery that feeds the tumor lesions at liver level (Geschwind, J. Vasc Intery Radiol. 2002; 13(10):991-4), into the right or left pulmonary artery that feeds the tumor lesions at lung level (Vogl T J. et al. Radiology 2005; 234:917-22). The embolic agents keep the chemotherapeutic agent in the tumor by blocking the flow to other areas of the body.
Currently, there is intense research activity in the area of nanotechnology and drug-delivery systems. The ideal drug-loaded carriers should deliver the agent precisely, release it in a controlled and sustained manner and achieve high intra-tumor drug concentration for a sufficient period, without damaging the surrounding normal tissue. Several drug-delivery systems for loco regional treatment of tumors, such as microspheres, have been recently tested (Constantin, M et al., Int J Pharm. 2004 Nov. 5; 285(1-2):87-96). Microspheres are essentially solid porous particles (50-1200 micrometer diameter), which can both target their drug cargo by physical trapping in blood vessels (chemoembolization) and sustain the action of a therapeutic agent through controlled release.
Microspheres can be made from a broad range of polymeric materials, such as polyvinyl alcohol (PVA), 2-acrylamido-2-methyl-1-1-propane-sulphonoc acid (AMPS), poly(lactide-co-glycolide) (FLOG).
In WO2004/071495 and WO2005/087193, microspheres are loaded with a single chemotherapeutic agent, such as doxorubicin, and infused intra-arterially for selective tumor targeting.
Sulphonate-modified N-Fil hydrogel microspheres (polyvinyl alcohol), trade name DC Bead™ (Biocompatibles) microspheres and so referred to herein below, are described as capable of loading doxorubicin in an article of Lewis et al (J. Vasc. Interv. Radiology; 2006; 17-335-442).
Trisacrylgelatin collagen-coated microspheres, trade name Embosphere® microspheres (BioSphere Medical), and expanding microspheres, trade name HepaSphere™ (BioSphere Medical), so referred to herein below, are described as capable of loading anticancer agents (Vallée J N et al. J Vasc Intery Radiol 2003; 14:621-8; Osuga K. et al. JVIR 2002; 13:929-34).
The critical determinants in defining the pharmacological activity of chemoembolization performed with microspheres are represented by:                preservation of the native conformation of the microspheres (in terms of size, spherical shape and plasticity), to guarantee the appropriate occlusion of the lumen of the vessel, avoiding distal embolization.        loading rate of the chemotherapeutic agents into the microspheres, to guarantee the administration of a therapeutic dose.        release rate of the chemotherapeutic agents from the microspheres, to guarantee the availability of the chemotherapeutic agents in a sustained manner and the achievement of high intra-tumor drug concentration for a sufficient period of time, without damaging the surrounding normal tissue.        kinetics of release of the chemotherapeutic agents from the microspheres, to guarantee a prolonged and complete release of the chemotherapeutic agents.        use of an appropriate amount of microspheres to guarantee the administration of an accurate dose of chemotherapeutic agent.        
The active drug substance incorporated in the system usually influences significantly the clinical performances of the microspheres by altering or modifying their physico-chemical parameters, such as, as example the particle size distribution, thus impacting on the expected occlusion of the lumen of the vessel, avoiding distal embolization (i.e. if the microsphere is shrunk by the presence of the drug, the risks of distal embolization are higher), the release kinetic of the active drug substance from the formulation and drug stability.
We have surprisingly found a way of overcoming all such drawbacks.